Depression is a mental illness characterized by a persistent low mood and reduced interest and energy levels, significantly impairing the quality of life (1, 2). The global prevalence of depression is approximately 5% (3). This condition profoundly impacts the physical and mental health of patients while also imposing substantial social and economic burdens. By 2030, depression is anticipated to become the leading cause of disease burden globally (4). Consequently, research on depression treatment remains a critical focus in the field of global health.

In clinical practice, depression is commonly associated with low mood, slow thinking, and reduced volitional activity. However, patients with depression often also experience varying degrees of sleep disorders, cognitive dysfunction, and executive dysfunction. Sleep disorders, which are one of the primary symptoms of depression, serve as a significant risk factor for the onset and progression of the condition (5). Sleep disorders and depression frequently co-occur, demonstrating a bidirectional relationship. Approximately 80-90% of individuals with depression report sleep disturbances (6, 7), which, in turn, can lead to negative emotions such as anxiety and tension, thereby exacerbating depression (6). Cognitive dysfunction is another critical symptom prevalent among patients with depression (8, 9). Even after depressive symptoms are alleviated, cognitive impairments may persist, affecting or limiting the patient's functional abilities in various areas and severely impacting their quality of life (10, 11). Furthermore, cognitive dysfunction can increase the risk of recurrent depression and reduce patient adherence to medication regimens (12). Therefore, it is essential to address not only the emotional symptoms of depression but also the cognitive impairments that may continue even after the depressive symptoms have improved. Executive function (13) is a subset of cognitive function involving the regulation and control of other cognitive processes necessary for completing complex tasks. It encompasses several key functions, including planning, judgment, decision-making, inhibition of inappropriate responses, and initiating and controlling goal-directed behaviours. This complex cognitive activity is significantly impacted by depression (14). Consequently, treatment for depression should not only address the patients' emotional symptoms but also their sleep quality, cognitive function, and particularly their executive function.

With the continuous advancement and development of medical science, the treatment options for severe depression have become increasingly diverse. However, they remain largely confined to drug therapy and psychological therapy. Although antidepressants are more effective than placebos and are widely used in clinical practice (15), only approximately 50% of patients with severe depression experience significant clinical improvement after taking these medications (16). Furthermore, issues such as stigma, side effects, economic burden, and potential addiction often lead to poor treatment adherence and interruptions, resulting in fluctuations or even worsening of the depression. In addition to medication, psychotherapy is also recommended as a first-line treatment in many depression guidelines (17–19). Nevertheless, the widespread implementation of psychological treatment is challenging due to its specialized nature, lengthy duration, and considerable economic burden. Therefore, it is crucial to explore new (combination) treatment methods to better address the needs of patients with severe depression.

In recent years, there has been increasing attention on the study of exercise therapy for depression (20–22). Both aerobic exercises and stretching or resistance training exercises have been shown to be effective in treating depression (23–29). However, there is limited research comparing the effects of stretching or resistance training exercises with aerobic exercises in the treatment of severe depression. To address this gap, we incorporated interventions of aerobic exercises therapy, stretching or resistance training exercises therapy, and non-exercise therapy into the conventional treatment for patients with severe depression. We conducted a comparative analysis of their clinical efficacy, aiming to provide a reference for developing exercises therapy prescriptions for patients with severe depression. In our research, the assessment of clinical efficacy not only includes the evaluation of depressive symptoms and sleep quality, but also encompasses the assessment of cognitive function, for exercise can be understood as a form of energetic mobilisation that, through cyclic engagement and recovery, promotes the restoration of attentional resources (30). While prior studies (31, 32) have explored exercise as an add-on treatment for depression, their focus has predominantly been on mild-to-moderate cases or lacked direct comparisons between aerobic exercises and stretching or resistance training exercises modalities. This study uniquely targets inpatients with severe depression, providing head-to-head comparisons of these exercise types alongside conventional treatment. In order to reduce the duration of depression and the impact of previous treatment, patients with first episode of severe depressive disorder were selected as the study subjects.

Figure 1 provides the CONSORT-style flow diagram of participant recruitment, allocation, and analysis, and includes the reasons for exclusion and attrition. Findings were consistent in the ITT sensitivity analyses including all 273 randomized participants; inferences did not materially change compared with the mITT results.

All pairwise comparisons for secondary endpoints were performed using one-way ANOVA and adjusted for multiplicity using Holm’s procedure (α=0.05). Unadjusted p-values are displayed in the table for simplicity. Unadjusted P-values are displayed in the table for simplicity. Endpoints surviving Holm are marked (†) in Table 1; the unadjusted and Holm-adjusted P-values are reported in Supplementary Table S2.

There were no exercise-related injuries or significant adverse events reported in either group. No participants withdrew due to exercise-related reasons.

Comparison of general clinical data among three groups.

No significant differences were noted in age [group A: group B: group C: (43.87 ± 13.46) years old: (40.52 ± 12.61) years old: (41.54 ± 13.52) years old, respectively; F = 1.327, P = 0.267], gender composition (male/female) [group A: group B: group C: 38/41:39/38:40/38, χ² = 0.178, P = 0.915] and duration of depression [group A: group B: group C: (12.32 ± 3.49) months: (11.96 ± 3.35) months: (11.88 ± 3.13) months, respectively; F = 0.377, P = 0.686] among the three groups.

No significant difference was noted in the composition of different drug types among the three groups (χ² = 5.915, P = 0.822) (see Table 2). No significant differences were noted in the dosage of the same drug among the three groups (all P > 0.05) (see Table 3).

Comparison of the scores of each scale in three groups before and after intervention. As is shown in Table 1.

Upon comparison of the scores of each scale in three groups before and after the intervention, we found that before the intervention, no statistically significant differences were noted in the scores of HAMD24, PSQI, MOCA, C-TMT, and SCWT among the three groups (all P > 0.05).

After intervention, scores of HAMD24, PSQI, C-TMT-A and C-TMT-B in three groups were all lower than those recorded before the intervention. Scores of MOCA, Stroop Word, Stroop Color and Stroop Color-Word were all higher than those recorded before the intervention, with statistically significant differences (all P < 0.05). For HAMD24, the scores of Group B (P = 0.015) and Group C (P = 0.030) were all lower than those of Group A. For PSQI, the scores of Group B (P = 0.027) and Group C (P = 0.032) were all lower than those of Group A. For MOCA, the scores of Group B (P<0.001) and Group C (P = 0.036) were all higher than those of Group A. Furthermore, the score of Group B (P = 0.039) was higher than that of Group C. For C-TMT-A, the scores of Group B (P = 0.017) and Group C (P = 0.037) were all lower than those of Group A. For C-TMT-B, the scores of Group B (P<0.001) and Group C (P = 0.021) were all lower than those of Group A. The score of Group B (P = 0.036) was lower than that of Group C. For Stroop Word, the scores of Group B (P = 0.010) and Group C (P = 0.033) were all higher than those of Group A. For Stroop Color, the scores of Group B (P = 0.013) and Group C (P = 0.037) were all higher than those of Group A. For Stroop Color-Word, the scores of Group B (P<0.001) and Group C (P = 0.038) were all higher than those of Group A. The score of Group B (P = 0.033) was higher than that of Group C. Conclusions were unchanged in sensitivity checks; secondary endpoints also remained significant after Holm adjustment where indicated in Table 1.

Descriptive change scores (Supplementary Table S1) showed patterns consistent with greater improvement in both exercise arms relative to Group A.

Attendance, session duration, and intensity adherence data are summarized for each intervention group in Table 4. For the aerobic arm, adherence to the target HR zone was monitored, and for the resistance/stretching arm, intensity was standardized by RPE and progression scheme.

Given the high prevalence of depression, the serious consequences of severe depression, and the constraints associated with conventional medication and psychotherapeutic approaches, we designed this study. Our aim was to assess the potential synergistic impact of exercise alongside pharmacological treatment for severe depression, focusing on enhancements in depression severity, sleep quality, and cognitive function. Additionally, we sought to compare and analyse the synergistic effects of aerobic exercises and stretching or resistance training exercises. Our ultimate objective is to identify a more efficacious and cost-effective intervention for the management of severe depression, thereby offering valuable insights into its treatment.

Our findings align with Imboden et al. (31), who reported comparable antidepressant effects of aerobic exercises and stretching. However, our study extends these results by demonstrating that stretching or resistance training exercises also yields similar improvements in depressive symptoms, even in a severely ill population. This contrasts with Knapen et al. (32), who focused on broader mental health outcomes without stratifying by depression severity.

Regarding the improvement in depressive severity, the findings revealed that following the intervention, HAMD24 scores significantly decreased in all three groups compared to pre-intervention levels. Furthermore, patients in both combined treatment groups exhibited significantly lower HAMD24 scores compared to those in the conventional treatment group. Notably, there was no significant discrepancy in HAMD24 scores between the two combined treatment groups. Moreover, combining conventional treatment with either aerobic exercises or stretching or resistance training exercises yielded comparable effects in enhancing depressive severity, both surpassing the outcomes of conventional treatment alone. While numerous studies have investigated the beneficial effects of exercise on depressive severity in patients with depression, the majority have focused on individuals with mild to moderate depression (22, 40, 41), with an inclination towards aerobic exercises such as walking, jogging, and yoga (23, 42–44). In contrast, our study centred on patients with severe depression and delineated between aerobic and stretching or resistance training exercises regimens, offering a novel approach to understanding the impact of exercise on depression management. This approach provides valuable insights and complements existing research on exercise interventions for depression.

As the PSQI reflects sleep quality over the preceding month, which partially overlaps with the baseline→post-treatment windows of the 6-week trial, this temporal overlap should be considered when interpreting sleep outcomes at the 6-week timepoint. This overlap may influence the extent to which changes in sleep quality directly reflect the intervention's immediate effects. Regarding the enhancement of sleep quality, the results demonstrated that following the intervention, PSQI scores significantly decreased in all three groups compared to pre-intervention levels. Additionally, patients in both combined treatment groups exhibited significantly lower PSQI scores compared to those in the conventional treatment group. Notably, there was no significant disparity in PSQI scores between the two combined treatment groups. These findings indicate that all three intervention methods substantially improved sleep quality in patients with severe depression. Furthermore, combining conventional treatment with either aerobic exercises or stretching or resistance training exercises yielded equivalent effects in enhancing sleep quality, both surpassing the outcomes of conventional treatment alone. Given that sleep disturbance is a prevalent and pertinent clinical symptom in individuals with depression and is also recognized as an independent risk factor for depression, interventions for depression should encompass not only the amelioration of mood but also the improvement of sleep quality (45). Network meta-analysis has indicated that exercise, as an adjunctive therapy, significantly enhances sleep quality in patients with depression, irrespective of whether it is aerobic exercises or stretching or resistance training exercises (46). This finding is generally in line with the outcomes of our study. In contrast to our study, which specifically targeted patients with severe depression, this network meta-analysis failed to conduct a more refined investigation into depression severity. Moreover, it revealed that moderate aerobic exercise alone did not significantly enhance sleep quality in patients with depression. Unfortunately, the meta-analysis did not include an exercise-only intervention group due to the pressing need to address severe depression in patients. Consequently, our study solely examined the supplementary effects of aerobic exercises or stretching or resistance training exercises. Considering the pivotal role of sleep disturbances in the onset, progression, and prognosis of depression, enhancing sleep quality holds significant implications for the recovery of patients with severe depression (45). Therefore, for individuals with severe depression experiencing sleep problems, in addition to pharmacological interventions such as sleeping pills, the inclusion of aerobic exercises or stretching or resistance training exercises as adjunctive therapies alongside existing treatments may offer valuable support in improving their sleep quality.

Regarding the enhancement of cognitive function, the findings indicated that following the intervention, MOCA scores significantly increased in all three groups compared to pre-intervention levels. Additionally, patients in both combined treatment groups exhibited significantly higher MOCA scores compared to those in the conventional treatment group. Furthermore, the MOCA score of patients in Group B was significantly higher than that in Group C. As MOCA is commonly utilized to assess an individual's global cognitive function, our study underscores that all three intervention methods significantly improve global cognitive function in patients with severe depression, with both combined treatment approaches outperforming conventional treatment alone. Moreover, within the combined treatment groups, conventional treatment combined with aerobic exercises demonstrated superior efficacy compared to conventional treatment combined with stretching or resistance training exercises. These findings align with a study investigating the effects of exercise therapy on global cognitive function and depression in older adults with mild cognitive impairment, which suggested that aerobic exercise was the most effective in enhancing cognitive function when compared to other forms of exercise (47). In contrast to a study (48) suggesting that exercise did not yield improvements in cognitive function among patients with depression, a considerable body of research (31, 49, 50) supports the notion that aerobic exercise significantly enhances cognitive function in this population. However, inconsistent conclusions across studies may stem from variations in subject heterogeneity and differences in exercise modality, intensity, frequency, and intervention duration.

Unlike prior investigations, our study focused specifically on patients with severe depression and examined the efficacy of stretching or resistance training exercises when combined with conventional antidepressant treatment. This unique approach renders our findings more directly applicable to this specific population. Regarding the enhancement of global cognitive function in patients with severe depression, our results indicate that conventional treatment combined with aerobic exercises yields the most pronounced benefits, followed by conventional treatment combined with stretching or resistance training exercises, both surpassing the outcomes of conventional treatment alone.

Cognitive dysfunction constitutes a significant aspect of depression symptomatology, particularly prominent in individuals with severe depression. Even following the remission of depressive symptoms, cognitive impairment may persist, which may inhibit and limit the functioning of patients in multiple fields, elevating the risk of depression recurrence, thereby negatively impacting depression prognosis (12, 30). Recognizing the pivotal role of cognitive dysfunction in depression management, alongside the utilization of MOCA to evaluate cognitive function, we also incorporated the C-TMT and SWCT to evaluate the cognitive function of the subjects. We aimed to obtain more detailed insights. As depicted in Table 1, all three intervention methods significantly enhanced cognitive function in patients with severe depression. Specifically, improvements in cognitive function, as measured by C-TMT-A, Stroop Word, and Stroop Color tests, were more pronounced in the two combined treatment groups compared to the conventional treatment group. However, no significant differences were observed between the two combined treatment groups in these cognitive domains. In contrast to the aforementioned findings, when assessing cognitive function using the C-TMT-B and Stroop Color-Word tests, it was observed that conventional treatment combined with aerobic exercises exhibited the most favourable outcomes, followed by conventional treatment combined with stretching or resistance training exercises. Both of these combined interventions surpassed the efficacy of conventional treatment alone. In the C-TMT assessment (38), Part A serves as a reliable measure of psychomotor speed and visual attention, while Part B is commonly utilized to evaluate executive function, cognitive flexibility, and set-shifting abilities. Conversely, in SWCT (39), the Stroop Word and Stroop Color tasks primarily evaluate the speed of information processing, whereas the Stroop Color-Word task assesses selective attention, cognitive flexibility, and inhibitory control. When considering these findings alongside the comprehensive results presented in Table 1, it becomes apparent that for improving executive function, cognitive flexibility, set-shifting abilities, selective attention, and inhibitory control among patients with severe depression, conventional treatment combined with aerobic exercises demonstrates superior efficacy, similar to the research findings of Zhang's work (51) and Schumann's work (30). This is followed by conventional treatment combined with stretching or resistance training exercises, both of which outperform conventional treatment alone. A minor distinction arises when considering the enhancement of psychomotor speed, visual attention, and speed of information processing. Here, the effectiveness of conventional treatment combined with aerobic exercises aligns closely with that of conventional treatment combined with stretching or resistance training exercises, with both combinations exhibiting superiority over conventional treatment alone. This convergence may reflect the fact that different exercise modalities can induce similar states of low physiological arousal, although the subjective quality of such states (e.g., feeling relaxed versus feeling tired) may differ (52). In summary, concerning the augmentation of cognitive function in patients with severe depression, combination therapies yield greater efficacy compared to conventional treatment alone. However, when focusing on the enhancement of executive function, cognitive flexibility, set-shifting abilities, selective attention, switching ability, and inhibitory control, conventional treatment combined with aerobic exercises emerges as superior to conventional treatment combined with stretching or resistance training exercises.

All groups received twice-weekly group psychotherapy sessions, ensuring equivalence in psychotherapy exposure. We acknowledge that hypnotics and benzodiazepines could have influenced sleep outcomes, but as these medications were monitored and used at the discretion of the treating physician, we did not collect detailed data on their use or dosing changes. Furthermore, psychotherapy exposure was consistent across all intervention arms, thus minimizing the potential for confounding by differential exposure.

No exercise-related adverse events occurred in either intervention arm, and no participants withdrew due to exercise-related issues. This suggests the interventions were safe and feasible for the inpatient population. However, safety and feasibility data are always essential for future studies to ensure the broader translation of these findings.

The study included participants aged 18 to 60 years who were receiving SSRI monotherapy for major depressive disorder at a single hospital. The findings of this study may not be directly applicable to older adults, patients receiving polypharmacy treatments, or those in different healthcare settings. Therefore, the generalizability of the results is limited to the specific population described.

In patients with severe depression, combining conventional treatment with either aerobic exercises or stretching or resistance training exercises demonstrated superiority over conventional treatment alone in enhancing depressive severity, sleep quality, and cognitive function. However, conventional treatment combined with aerobic exercises exhibited greater effectiveness than conventional treatment combined with stretching or resistance training exercises in improving certain aspects of cognitive function.

As such, the incorporation of suitable aerobic exercise into the clinical management of severe depression may be deemed beneficial. This approach not only enhances the clinical efficacy of antidepressant treatment to a certain extent but also mitigates the potential adverse reactions or economic burden associated with antidepressant drug therapy or psychological interventions.